1. Field of the Invention
The present invention relates to a pharmaceutical composition for improving sleep quality, and more specifically relates to a pharmaceutical composition comprising pharmaceutically effective amounts of an extract of the plant Valeriana officinalis L. (V. officinalis L) and methods of using such compositions to improve sleep quality, as measured via a variety of specific criteria.
2. Description of the Related Art
Extracts of the root of the plant Valeriana officinalis L. (V. officinalis L.) have been used for medicinal purposes for over a century. Certain valerian extracts, including aqueous extracts, are known to have sedative and anxiolytic effects, but the active components have not been clearly and positively identified. [Leathwood P. D., Chauffard F., Heck E., and Munoz-Box R. Aqueous extract of valerian root (Valeriana officinalis L.) improves sleep quality in man. Pharmacology, Biochemistry and Behavior, 17:65-71, 1982; Leathwood P. D. and Chauffard F. Aqueous extract of valerian reduces latency to fall asleep in man. Planta Medica, 2:144-148 (1985)]. Such effects are described, for example, by Balandrin et al. in U.S. Pat. No. 5,506,268, which is incorporated by reference herein in its entirety. Presently, valerian extracts are available as dietary supplements; these dietary supplements primarily comprise dried root or extracts from the root, formulated into tablets or soft gelatin capsules. Each dose contains between approximately 50 mg and approximately 1 gram of dried root or extract. The use of these dietary supplements is extensive, with an estimated 210 million doses sold annually in the United States and 125 million doses sold annually in Europe. See Grunwald, J., “The European Phytomedicines Market—Figures, Trends Analyses” Herbal Gram, 1995.
V. officinalis L. is a member of the Valerianaceae family. This plant grows from a short rhizome to approximately 2 meters in height, it flowers, and then dies back again in the winter. Valeriana officinalis L. has pinnately-divided leaves, typically with six to ten pairs of lance-shaped leaflets, and bears many small white or pink flowers in a dense head of several stalked clusters. These heads bare small (5 millimeters) tapered seeds.
It is not fully understood which constituents of Valeriana officinalis L., and/or of the other heretofore unidentified members of the Valerianaceae family, are responsible for the sedative and/or anxiolytic action of valerian extracts. Nonetheless, the valepotriates (iridoids) as well as valerenic acid, a sesquiterpenoid compound, and the derivatives of valerenic acid (for example, acetoxyvalerenic acid and hydroxyvalerenic acid) along with kessane derivatives, valeranone, valerenal, and certain amino acids are present in valerian extracts. Of these components, the valepotriates and valerenic acids are generally considered to contribute to the sedative action of valerian extracts, but have not been clearly and positively identified as such. See Hendriks H. et al. “Pharmacological Screening of valerenal and some other components of essential oil of Valeriana officinalis” Planta Medica 42, 62-68 (1981); Bos R. et al., “Analytical aspects of phytotherapeutic valerian.” (1996); Houghton P. J., Valerian. The Genus Valeriana. Harwood Academic Publishers, London (1997).
Valepotriates (iridoids) are triesters of polyalcohols with an iridoid structure. They are unstable, thermolabile compounds that decompose in alcoholic solutions and under acidic or alkaline conditions. See Bos R. et al. Analytical aspects of Phytotherapeutic Valerian preparation, 1996; 7:143-151. The major decomposition products of diene type valepotriates are baldrinals, including: baldrinal (from the valepotriates valtrate and acevaltrate) and homobaldrinal (from the valepotriate isovaltrate). Relative to the above-described valepotriates, valerenic acid and its derivatives (for example, acetoxyvalerenic acid and hydroxyvalerenic acid) are chemically stable. While valepotriates and valepotriate decomposition products or derivatives are found in many species of Valerianaceae, Valeriana officinalis L. is the only species that has been identified as possessing extractable valerenic acid in its roots. The structures of valerenic acids and certain valepotriates and valepotriate decomposition products are presented below. 
Several processes are known for the extraction of valerian roots, but none of these known processes simultaneously retains valerenic acid, maximizes the content of the valerenic acids (e.g., of valerenic acid and of the valerenic acid derivatives), and minimizes the content of valepotriates. Indeed, certain of these extraction processes were designed to retain or maximize the yield of valepotriates. For example, Broese et al., CH 000046778 (1978), describe obtaining a stable extract of a valerian preparation in which the essential valepotriates are present undiminished in the resultant extract, and Wischniewski et al., U.S. Pat. No. 4,313,930 (1982), describe the production of a stable valepotriate composition, through the use of a pharmaceutically acceptable sheathing material, from a pharmaceutically active Valerianacea extract. Other known extraction processes focus on removing the odors associated with the valepotriate and valepotriate derivatives, but do not maximize the content of valerenic acid and the valerenic acid derivatives.
For example, Cerise et al., U.S. Pat. No. 5,211,948 (1993), describe extracting Valerian roots with water over a period of 2 to 5 hours at a temperature from 65 to 75° C. This water-based extraction is described as leading “to degradation of the valepotriates while preserving the valerenic acids of the valerian roots.” The '948 patent also states that extraction of valerian roots with hot water (2 to 5 hrs at 65-75° C.), preferably three successive times, leads to degradation of the valepotriates while “preserving” the valerenic acids. However, the results of the current examples, see esp. Examples 6-10, indicate that the valerenic acids are “preserved” in the roots and are not extracted.
Valerenic acid is a chemically stable compound that is used as an identification test for V. officinalis in the United States Pharmacopoeia (USP23-NF18, Supplement 8). Thus, to develop a valerian based sedative product, it would be beneficial to enrich valerenic acids in the extract or substantially retain valerenic acid from the root. Due to poor solubility of valerenic acids in water, the process of the '948 Patent is inefficient in extracting these compounds. The extraction process of the present invention, on the other hand, efficiently enriches valerenic acids. In this respect, the present invention is far more superior than the Cerise process.
Other extraction processes are known, but are conducted in the presence of unusual, expensive, or otherwise undesirable solvents and/or at unusual or undesirable conditions, such as low pH. For example, Thies et al., U.S. Pat. No. 3,422,090 (1969) describe extracting roots and rhizomes of plants of the genus Valeriana at a temperature below 30° C. with a lipophilic solvent in the presence of an aliphatic carboxylic acid, specifically glacial acidic acid, within a pH range of about 3 to about 7. Gehrlicher, DE 03112737 (Mar. 31, 1981) (“the '737 application”) describes obtaining epoxide-free sedative agents from plants of the Valerianaceae family by extracting at elevated temperatures in the presence of weak acids and catalytic amounts of strong acids at pH<3, with either lower aliphatic alcohols or mixtures of lower aliphatic alcohols with water or anhydrous non-polar solvents. The process of the '737 application, however, retains baldrinals and other valepotriate decomposition products in the extract.